Sex Differences in Domain-Specific Cognitive Trajectories and Dementia Risk: Evidence From the Whitehall II Cohort

Evidence on sex differences in cognition and dementia is inconsistent, and it is unclear whether such differences are explained by dementia risk factors.

To assess (i) sex differences in cognitive decline and dementia risk, (ii) the extent to which modifiable and nonmodifiable risk factors explain these differences and (iii) whether birth cohort and apolipoprotein (APOE)-Ꜫ4 carrier status modify sex differences in cognitive decline.

Data from the Whitehall II study were analysed to examine cross-sectional and longitudinal associations between sex, cognitive decline and dementia risk. Cognitive outcomes included verbal memory and verbal fluency, assessed from Phase 5 onward, with over 16 years of follow-up. Test scores were standardised using means and standard deviations from the baseline cognitive tests to generate z-scores. All-cause dementia was ascertained through linkage to three electronic health record databases.

Among 5920 participants aged 44.8-68.2 years, women demonstrated better baseline performance than men in memory (adjusted mean difference = -0.2, p < 0.0001), phonemic fluency (-0.1, p = 0.001) and semantic fluency (-0.2, p < 0.0001). Men exhibited a steeper decline in semantic fluency (adjusted β = -2.6, p < 0.0001) and a nominal decline in phonemic fluency (-1.7, p = 0.007). Sex differences remained after adjustment for covariates. Dementia incidence did not differ significantly by sex. Birth cohort and APOE-Ꜫ4 carrier status did not meaningfully modify associations between sex and cognitive outcomes.

Cognitive advantages observed in women in midlife did not translate into lower dementia risk. Further research incorporating biological, psychosocial and life-course factors, as well as the timing and heterogeneity of underlying disease processes, is needed to better understand sex differences in cognitive ageing and dementia.